In Focus

 

Inflammatory bowel disease (IBD) consists of two chronic inflammatory diseases, Crohn’s disease (CD) and ulcerative colitis (UC), as well as a small category of patients (~10%) who have atypical features called IBD-unclassified (IBD-U) or indeterminate colitis. The prevalence of IBD ranges from 0.3% to 0.5% overall in North America and Europe.¹ In North America, the incidences of CD and UC are estimated to be 3.1 to 14.6 per 100,000 person-years and 2.2 to 14.3 cases per 100,000 person-years, respectively; similar rates are seen in Europe.² However, incidences up to 19.2 and 20.2 per 100,000 for UC and CD, respectively, have been reported in Canada.3^,4 The incidences of both UC and CD are increasing over time in Western countries and in rapidly industrializing countries throughout Asia and South America.^5-8

With the increased incidence and advances in the treatment of IBD, many more patients are being treated with corticosteroids, immunomodulators, and biologics. Over time, there has also evolved an understanding of the importance of health maintenance in IBD patients, especially since patients with IBD receive fewer recommended preventive health services than general medical patients even though the use of immunosuppression is an argument for more attention to these issues.⁹ Gastroenterologists may see patients more frequently than their primary care provider (PCP) or PCPs may be unaware of the specific needs of IBD patients. Therefore, it is important that gastroenterologists are knowledgeable about the health maintenance recommendations that can be made to patients and to communicate these to PCPs. Recent society guidelines endorse the importance of this aspect of our practice.¹⁰ The discussion below highlights health maintenance issues that should be fundamental aspects of our IBD practices, however it does not address colon cancer screening and surveillance since these are beyond the scope of this article.
 

Influenza vaccine and pneumococcal vaccine

Influenza A and B outbreaks are commonly seen during the fall and early spring and risk factors for pneumonia and hospitalization include older age, chronic medical conditions, and immunosuppression. The CDC now recommend annual influenza vaccination for all individuals older than six months. For patients on immunosuppression, the vaccine administered should be the inactivated vaccine, as live attenuated vaccines should not be administered to these patients.

Copyright Shawn Rocco

Patients with IBD are also at an increased risk of bacterial pneumonia, the most common etiology of which is pneumococcal pneumonia.¹¹ The Advisory Committee on Immunization Practices (ACIP) recommends that patients on immunosuppression receive a one-time dose of the pneumococcal conjugate vaccine PCV13, followed by a dose of the pneumococcal polysaccharide vaccine PPSV23 one year later (eight weeks at the earliest). A second dose of PPSV23 should be given five years later and a third dose after 65 years of age.

In IBD patients, the influenza and pneumococcal vaccines are both well tolerated without an increased rate of adverse effects over the general population and without an increased risk of IBD flares after vaccination.¹² A common question for patients on biologic therapy is whether the vaccine should be timed at a specific point in the dose cycle. For infliximab, and likely other biologics, the timing does not change the vaccine immunogenicity and patients should be given these vaccines regardless of where they are in the cycle of administration of their biologic.¹³ In addition, there is significant response to influenza and pneumococcal vaccines in patients on combination therapy with immunomodulators and anti-TNFs and concerns about a lack of response to vaccines should not discourage vaccination since benefits are still acquired by patients even if immunogenicity is somewhat decreased.^14,15

Other vaccinations

In addition to the influenza and pneumococcal vaccines, adult and pediatric patients with IBD should follow the ACIP recommendations for tetanus, diphtheria, pertussis (Tdap), Td boosters, hepatitis A, hepatitis B, human papilloma virus (HPV), and meningococcal vaccinations.^16,17

Live vaccines including measles mumps rubella (MMR), varicella, and zoster vaccines are in general contraindicated in immunosuppressed patients on corticosteroids, azathioprine/6-mercaptopurine, methotrexate, anti-TNF, and anti-integrin biologics. An inactive varicella-zoster vaccine will likely be available in the near future and may obviate the need for the live vaccine, which is an important development given the increased risk of zoster in patients with IBD on immunosuppression.¹⁸

Osteoporosis screening

Copyright Shawn Rocco

Both men and women with IBD have an elevated risk of osteoporosis and osteopenia as well as elevated fracture risk.¹⁹ This is related to frequent chronic corticosteroid use, chronic inflammation (high disease activity), women with low BMI, smoking, older age (women > 65, men >70), terminal ileal disease or resection in patients with CD, and proctocolectomy and ileal pouch-anal anastomosis in patients with UC. The recommendations are to obtain baseline bone density evaluation only in patients with risk factors, including young patients since osteopenia can be present at a young age. If If osteopenia is noted, then calcium (1000-1200mg daily) and vitamin D (1000-4000IU daily) supplementation can be associated with improvement in osteopenia.²⁰ If osteoporosis is noted, patients should be referred to rheumatology or endocrinology for evaluation for bisphosphonate therapy which is also associated with improved outcomes.²¹ Bone density testing should be repeated every two years in patients with osteoporosis on treatment and less frequently when there is improvement.²² Given the association of bone metabolism disorders with smoking, this is one more reason to encourage our patients to quit.

 

Skin cancer screening

Multiple studies have demonstrated that immunosuppression, especially with methotrexate and azathioprine/6-mercaptopurine (6MP) is a risk factor for the development of initial and recurrent non-melanoma skin cancer (NMSC) in IBD patients, the data for biologics are less definitive.^23-25 In addition, biologics are associated with increased risk of melanoma in IBD.²⁶ The elevated risk of skin cancer begins in the first year of treatment with thiopurines and may continue after discontinuation. On the basis of this data, screening for melanoma and NMSC is recommended in IBD patients on immunosuppression. Especially for patients on thiopurines it is reasonable for the initial dermatologist visit to occur in the first year of treatment and thereafter with at least annual visits for a full body skin examination. In addition, it is reasonable to recommend regular sunscreen use and protective clothing such as hats.

Cervical cancer screening

A recent meta-analysis shows that women with IBD on immunosuppression have an increased risk of cervical high grade dysplasia and cervical cancer.²⁷ HPV is the major risk factor for cervical cancer and is necessary for its development. The current American College of Gynecology guidelines for women on immunosuppression are to start cervical cancer screening at 21 and annual screening thereafter with Pap and HPV testing.²⁸

Smoking

Smoking has well known associations with poor outcomes in the general population such as increased risk of lung and pancreatic cancers, as well as high risk of cardiovascular disease. In addition, smoking has risks specific to IBD. In CD, smoking is associated with increased disease activity, increased risk of post-operative recurrence, and increased severity of disease.²⁹ Smoking cessation is associated with improved long-term disease outcomes and less risk.³⁰ Making it a point to regularly discuss smoking cessation and partnering with PCPs to offer evidence-based quitting aids may be one of our most significant and beneficial interventions.

Depression and anxiety

Several studies have shown high levels of depression and anxiety in IBD patients and higher levels of depression are associated with increased symptoms, clinical recurrence, poor quality of life and decreased social support.^31-33 A recent systematic review of several studies suggested that antidepressants use in IBD patients benefits their mental health and may improve their clinical course as well.³⁴ As such, screening for depression and anxiety regularly and either offering treatment or referral to psychiatrists and psychologists for further management is recommended.¹⁰

Conclusion

Patients with IBD frequently develop long-term relationships with their gastroenterologists due to their lifelong chronic disease. It is therefore incumbent on us to be attentive to issues related to IBD patients’ preventive care and collaborate with PCPs to coordinate care for our patients since many of these interventions have both short-term and long-term benefits.

Dr. Chachu is assistant professor and gastroenterologist at Duke University, Durham, N.C.

References

1. Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017;152(2):313-21.e2.

2. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17.

3. Bernstein CN, Wajda A, Svenson LW, et al. The Epidemiology of Inflammatory Bowel Disease in Canada: A Population-Based Study. The American journal of gastroenterology. 2006;101(7):1559-68.

4. Lowe AM, Roy PO, M BP, et al. Epidemiology of Crohn’s disease in Quebec, Canada. Inflammatory bowel diseases. 2009;15(3):429-35.

5. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2007;5(12):1424-9.

6. Kappelman MD, Moore KR, Allen JK, et al. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Digestive diseases and sciences. 2013;58(2):519-25.

7. Ng SC, Kaplan G, Banerjee R, et al. 78 Incidence and Phenotype of Inflammatory Bowel Disease From 13 Countries in Asia-Pacific: Results From the Asia-Pacific Crohn’s and Colitis Epidemiologic Study 2011-2013. Gastroenterology.150(4):S21.

8. Parente JML, Coy CSR, Campelo V, et al. Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil. World Journal of Gastroenterology : WJG. 2015;21(4):1197-206.

9. Selby L, Kane S, Wilson J, et al. Receipt of preventive health services by IBD patients is significantly lower than by primary care patients. Inflammatory bowel diseases. 2008;14(2):253-8.

10. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease. The American journal of gastroenterology. 2017;112(2):241-58.

11. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. The American journal of gastroenterology. 2013;108(2):240-8.

12. Rahier JF, Papay P, Salleron J, et al. H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy. Gut. 2011;60(4):456-62.

13. deBruyn J, Fonseca K, Ghosh S, et al. Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial. Inflammatory bowel diseases. 2016;22(3):638-47.

14. Brezinschek HP, Hofstaetter T, Leeb BF, et al. Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate. Current opinion in rheumatology. 2008;20(3):295-9.

15. Kaine JL, Kivitz AJ, Birbara C, et al. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J Rheumatol. 2007;34(2):272-9.

16. Kim DK, Riley LE, Harriman KH, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):136-8.

17. Robinson CL, Romero JR, Kempe A, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):134-5.

18. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflammatory bowel diseases. 2012;18(12):2392-403.

19. Card T, West J, Hubbard R, et al. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut. 2004;53(2):251-5.

20. Casals-Seoane F, Chaparro M, Mate J, et al. Clinical Course of Bone Metabolism Disorders in Patients with Inflammatory Bowel Disease: A 5-Year Prospective Study. Inflammatory bowel diseases. 2016;22(8):1929-36.

21. Melek J, Sakuraba A. Efficacy and safety of medical therapy for low bone mineral density in patients with inflammatory bowel disease: a meta-analysis and systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12(1):32-44.e5.

22. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International. 2014;25(10):2359-81.

23. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141(5):1621-28.e1-5.

24. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2010;8(3):268-74.

25. Scott FI, Mamtani R, Brensinger CM, et al. Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. JAMA dermatology. 2016;152(2):164-72.

26. Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143(2):390-9.e1.

27. Allegretti JR, Barnes EL, Cameron A. Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis. Inflammatory bowel diseases. 2015;21(5):1089-97.

28. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention. Obstetrics and gynecology. 2016;128(4):e111-30.

29. Ryan WR, Allan RN, Yamamoto T, et al. Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. American journal of surgery. 2004;187(2):219-25.

30. Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120(5):1093-9.

31. Fuller-Thomson E, Sulman J. Depression and inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflammatory bowel diseases. 2006;12(8):697-707.

32. Walker EA, Gelfand MD, Gelfand AN, et al. The relationship of current psychiatric disorder to functional disability and distress in patients with inflammatory bowel disease. General hospital psychiatry. 1996;18(4):220-9.

33. Mikocka-Walus A, Pittet V, Rossel J-B, et al. Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology.14(6):829-35.e1.

34. Macer BJD, Prady SL, Mikocka-Walus A. Antidepressants in Inflammatory Bowel Disease: A Systematic Review. Inflammatory bowel diseases. 2017;23(4):534-50.

 

Inflammatory bowel disease (IBD) consists of two chronic inflammatory diseases, Crohn’s disease (CD) and ulcerative colitis (UC), as well as a small category of patients (~10%) who have atypical features called IBD-unclassified (IBD-U) or indeterminate colitis. The prevalence of IBD ranges from 0.3% to 0.5% overall in North America and Europe.¹ In North America, the incidences of CD and UC are estimated to be 3.1 to 14.6 per 100,000 person-years and 2.2 to 14.3 cases per 100,000 person-years, respectively; similar rates are seen in Europe.² However, incidences up to 19.2 and 20.2 per 100,000 for UC and CD, respectively, have been reported in Canada.3^,4 The incidences of both UC and CD are increasing over time in Western countries and in rapidly industrializing countries throughout Asia and South America.^5-8

With the increased incidence and advances in the treatment of IBD, many more patients are being treated with corticosteroids, immunomodulators, and biologics. Over time, there has also evolved an understanding of the importance of health maintenance in IBD patients, especially since patients with IBD receive fewer recommended preventive health services than general medical patients even though the use of immunosuppression is an argument for more attention to these issues.⁹ Gastroenterologists may see patients more frequently than their primary care provider (PCP) or PCPs may be unaware of the specific needs of IBD patients. Therefore, it is important that gastroenterologists are knowledgeable about the health maintenance recommendations that can be made to patients and to communicate these to PCPs. Recent society guidelines endorse the importance of this aspect of our practice.¹⁰ The discussion below highlights health maintenance issues that should be fundamental aspects of our IBD practices, however it does not address colon cancer screening and surveillance since these are beyond the scope of this article.
 

Influenza vaccine and pneumococcal vaccine

Influenza A and B outbreaks are commonly seen during the fall and early spring and risk factors for pneumonia and hospitalization include older age, chronic medical conditions, and immunosuppression. The CDC now recommend annual influenza vaccination for all individuals older than six months. For patients on immunosuppression, the vaccine administered should be the inactivated vaccine, as live attenuated vaccines should not be administered to these patients.

Copyright Shawn Rocco

Patients with IBD are also at an increased risk of bacterial pneumonia, the most common etiology of which is pneumococcal pneumonia.¹¹ The Advisory Committee on Immunization Practices (ACIP) recommends that patients on immunosuppression receive a one-time dose of the pneumococcal conjugate vaccine PCV13, followed by a dose of the pneumococcal polysaccharide vaccine PPSV23 one year later (eight weeks at the earliest). A second dose of PPSV23 should be given five years later and a third dose after 65 years of age.

In IBD patients, the influenza and pneumococcal vaccines are both well tolerated without an increased rate of adverse effects over the general population and without an increased risk of IBD flares after vaccination.¹² A common question for patients on biologic therapy is whether the vaccine should be timed at a specific point in the dose cycle. For infliximab, and likely other biologics, the timing does not change the vaccine immunogenicity and patients should be given these vaccines regardless of where they are in the cycle of administration of their biologic.¹³ In addition, there is significant response to influenza and pneumococcal vaccines in patients on combination therapy with immunomodulators and anti-TNFs and concerns about a lack of response to vaccines should not discourage vaccination since benefits are still acquired by patients even if immunogenicity is somewhat decreased.^14,15

Other vaccinations

In addition to the influenza and pneumococcal vaccines, adult and pediatric patients with IBD should follow the ACIP recommendations for tetanus, diphtheria, pertussis (Tdap), Td boosters, hepatitis A, hepatitis B, human papilloma virus (HPV), and meningococcal vaccinations.^16,17

Live vaccines including measles mumps rubella (MMR), varicella, and zoster vaccines are in general contraindicated in immunosuppressed patients on corticosteroids, azathioprine/6-mercaptopurine, methotrexate, anti-TNF, and anti-integrin biologics. An inactive varicella-zoster vaccine will likely be available in the near future and may obviate the need for the live vaccine, which is an important development given the increased risk of zoster in patients with IBD on immunosuppression.¹⁸

Osteoporosis screening

Copyright Shawn Rocco

Both men and women with IBD have an elevated risk of osteoporosis and osteopenia as well as elevated fracture risk.¹⁹ This is related to frequent chronic corticosteroid use, chronic inflammation (high disease activity), women with low BMI, smoking, older age (women > 65, men >70), terminal ileal disease or resection in patients with CD, and proctocolectomy and ileal pouch-anal anastomosis in patients with UC. The recommendations are to obtain baseline bone density evaluation only in patients with risk factors, including young patients since osteopenia can be present at a young age. If If osteopenia is noted, then calcium (1000-1200mg daily) and vitamin D (1000-4000IU daily) supplementation can be associated with improvement in osteopenia.²⁰ If osteoporosis is noted, patients should be referred to rheumatology or endocrinology for evaluation for bisphosphonate therapy which is also associated with improved outcomes.²¹ Bone density testing should be repeated every two years in patients with osteoporosis on treatment and less frequently when there is improvement.²² Given the association of bone metabolism disorders with smoking, this is one more reason to encourage our patients to quit.

 

Skin cancer screening

Multiple studies have demonstrated that immunosuppression, especially with methotrexate and azathioprine/6-mercaptopurine (6MP) is a risk factor for the development of initial and recurrent non-melanoma skin cancer (NMSC) in IBD patients, the data for biologics are less definitive.^23-25 In addition, biologics are associated with increased risk of melanoma in IBD.²⁶ The elevated risk of skin cancer begins in the first year of treatment with thiopurines and may continue after discontinuation. On the basis of this data, screening for melanoma and NMSC is recommended in IBD patients on immunosuppression. Especially for patients on thiopurines it is reasonable for the initial dermatologist visit to occur in the first year of treatment and thereafter with at least annual visits for a full body skin examination. In addition, it is reasonable to recommend regular sunscreen use and protective clothing such as hats.

Cervical cancer screening

A recent meta-analysis shows that women with IBD on immunosuppression have an increased risk of cervical high grade dysplasia and cervical cancer.²⁷ HPV is the major risk factor for cervical cancer and is necessary for its development. The current American College of Gynecology guidelines for women on immunosuppression are to start cervical cancer screening at 21 and annual screening thereafter with Pap and HPV testing.²⁸

Smoking

Smoking has well known associations with poor outcomes in the general population such as increased risk of lung and pancreatic cancers, as well as high risk of cardiovascular disease. In addition, smoking has risks specific to IBD. In CD, smoking is associated with increased disease activity, increased risk of post-operative recurrence, and increased severity of disease.²⁹ Smoking cessation is associated with improved long-term disease outcomes and less risk.³⁰ Making it a point to regularly discuss smoking cessation and partnering with PCPs to offer evidence-based quitting aids may be one of our most significant and beneficial interventions.

Depression and anxiety

Several studies have shown high levels of depression and anxiety in IBD patients and higher levels of depression are associated with increased symptoms, clinical recurrence, poor quality of life and decreased social support.^31-33 A recent systematic review of several studies suggested that antidepressants use in IBD patients benefits their mental health and may improve their clinical course as well.³⁴ As such, screening for depression and anxiety regularly and either offering treatment or referral to psychiatrists and psychologists for further management is recommended.¹⁰

Conclusion

Patients with IBD frequently develop long-term relationships with their gastroenterologists due to their lifelong chronic disease. It is therefore incumbent on us to be attentive to issues related to IBD patients’ preventive care and collaborate with PCPs to coordinate care for our patients since many of these interventions have both short-term and long-term benefits.

Dr. Chachu is assistant professor and gastroenterologist at Duke University, Durham, N.C.

References

1. Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017;152(2):313-21.e2.

2. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17.

3. Bernstein CN, Wajda A, Svenson LW, et al. The Epidemiology of Inflammatory Bowel Disease in Canada: A Population-Based Study. The American journal of gastroenterology. 2006;101(7):1559-68.

4. Lowe AM, Roy PO, M BP, et al. Epidemiology of Crohn’s disease in Quebec, Canada. Inflammatory bowel diseases. 2009;15(3):429-35.

5. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2007;5(12):1424-9.

6. Kappelman MD, Moore KR, Allen JK, et al. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Digestive diseases and sciences. 2013;58(2):519-25.

7. Ng SC, Kaplan G, Banerjee R, et al. 78 Incidence and Phenotype of Inflammatory Bowel Disease From 13 Countries in Asia-Pacific: Results From the Asia-Pacific Crohn’s and Colitis Epidemiologic Study 2011-2013. Gastroenterology.150(4):S21.

8. Parente JML, Coy CSR, Campelo V, et al. Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil. World Journal of Gastroenterology : WJG. 2015;21(4):1197-206.

9. Selby L, Kane S, Wilson J, et al. Receipt of preventive health services by IBD patients is significantly lower than by primary care patients. Inflammatory bowel diseases. 2008;14(2):253-8.

10. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease. The American journal of gastroenterology. 2017;112(2):241-58.

11. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. The American journal of gastroenterology. 2013;108(2):240-8.

12. Rahier JF, Papay P, Salleron J, et al. H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy. Gut. 2011;60(4):456-62.

13. deBruyn J, Fonseca K, Ghosh S, et al. Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial. Inflammatory bowel diseases. 2016;22(3):638-47.

14. Brezinschek HP, Hofstaetter T, Leeb BF, et al. Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate. Current opinion in rheumatology. 2008;20(3):295-9.

15. Kaine JL, Kivitz AJ, Birbara C, et al. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J Rheumatol. 2007;34(2):272-9.

16. Kim DK, Riley LE, Harriman KH, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):136-8.

17. Robinson CL, Romero JR, Kempe A, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):134-5.

18. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflammatory bowel diseases. 2012;18(12):2392-403.

19. Card T, West J, Hubbard R, et al. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut. 2004;53(2):251-5.

20. Casals-Seoane F, Chaparro M, Mate J, et al. Clinical Course of Bone Metabolism Disorders in Patients with Inflammatory Bowel Disease: A 5-Year Prospective Study. Inflammatory bowel diseases. 2016;22(8):1929-36.

21. Melek J, Sakuraba A. Efficacy and safety of medical therapy for low bone mineral density in patients with inflammatory bowel disease: a meta-analysis and systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12(1):32-44.e5.

22. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International. 2014;25(10):2359-81.

23. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141(5):1621-28.e1-5.

24. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2010;8(3):268-74.

25. Scott FI, Mamtani R, Brensinger CM, et al. Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. JAMA dermatology. 2016;152(2):164-72.

26. Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143(2):390-9.e1.

27. Allegretti JR, Barnes EL, Cameron A. Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis. Inflammatory bowel diseases. 2015;21(5):1089-97.

28. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention. Obstetrics and gynecology. 2016;128(4):e111-30.

29. Ryan WR, Allan RN, Yamamoto T, et al. Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. American journal of surgery. 2004;187(2):219-25.

30. Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120(5):1093-9.

31. Fuller-Thomson E, Sulman J. Depression and inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflammatory bowel diseases. 2006;12(8):697-707.

32. Walker EA, Gelfand MD, Gelfand AN, et al. The relationship of current psychiatric disorder to functional disability and distress in patients with inflammatory bowel disease. General hospital psychiatry. 1996;18(4):220-9.

33. Mikocka-Walus A, Pittet V, Rossel J-B, et al. Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology.14(6):829-35.e1.

34. Macer BJD, Prady SL, Mikocka-Walus A. Antidepressants in Inflammatory Bowel Disease: A Systematic Review. Inflammatory bowel diseases. 2017;23(4):534-50.

 

Inflammatory bowel disease (IBD) consists of two chronic inflammatory diseases, Crohn’s disease (CD) and ulcerative colitis (UC), as well as a small category of patients (~10%) who have atypical features called IBD-unclassified (IBD-U) or indeterminate colitis. The prevalence of IBD ranges from 0.3% to 0.5% overall in North America and Europe.¹ In North America, the incidences of CD and UC are estimated to be 3.1 to 14.6 per 100,000 person-years and 2.2 to 14.3 cases per 100,000 person-years, respectively; similar rates are seen in Europe.² However, incidences up to 19.2 and 20.2 per 100,000 for UC and CD, respectively, have been reported in Canada.3^,4 The incidences of both UC and CD are increasing over time in Western countries and in rapidly industrializing countries throughout Asia and South America.^5-8

With the increased incidence and advances in the treatment of IBD, many more patients are being treated with corticosteroids, immunomodulators, and biologics. Over time, there has also evolved an understanding of the importance of health maintenance in IBD patients, especially since patients with IBD receive fewer recommended preventive health services than general medical patients even though the use of immunosuppression is an argument for more attention to these issues.⁹ Gastroenterologists may see patients more frequently than their primary care provider (PCP) or PCPs may be unaware of the specific needs of IBD patients. Therefore, it is important that gastroenterologists are knowledgeable about the health maintenance recommendations that can be made to patients and to communicate these to PCPs. Recent society guidelines endorse the importance of this aspect of our practice.¹⁰ The discussion below highlights health maintenance issues that should be fundamental aspects of our IBD practices, however it does not address colon cancer screening and surveillance since these are beyond the scope of this article.
 

Influenza vaccine and pneumococcal vaccine

Influenza A and B outbreaks are commonly seen during the fall and early spring and risk factors for pneumonia and hospitalization include older age, chronic medical conditions, and immunosuppression. The CDC now recommend annual influenza vaccination for all individuals older than six months. For patients on immunosuppression, the vaccine administered should be the inactivated vaccine, as live attenuated vaccines should not be administered to these patients.

Copyright Shawn Rocco

Patients with IBD are also at an increased risk of bacterial pneumonia, the most common etiology of which is pneumococcal pneumonia.¹¹ The Advisory Committee on Immunization Practices (ACIP) recommends that patients on immunosuppression receive a one-time dose of the pneumococcal conjugate vaccine PCV13, followed by a dose of the pneumococcal polysaccharide vaccine PPSV23 one year later (eight weeks at the earliest). A second dose of PPSV23 should be given five years later and a third dose after 65 years of age.

In IBD patients, the influenza and pneumococcal vaccines are both well tolerated without an increased rate of adverse effects over the general population and without an increased risk of IBD flares after vaccination.¹² A common question for patients on biologic therapy is whether the vaccine should be timed at a specific point in the dose cycle. For infliximab, and likely other biologics, the timing does not change the vaccine immunogenicity and patients should be given these vaccines regardless of where they are in the cycle of administration of their biologic.¹³ In addition, there is significant response to influenza and pneumococcal vaccines in patients on combination therapy with immunomodulators and anti-TNFs and concerns about a lack of response to vaccines should not discourage vaccination since benefits are still acquired by patients even if immunogenicity is somewhat decreased.^14,15

Other vaccinations

In addition to the influenza and pneumococcal vaccines, adult and pediatric patients with IBD should follow the ACIP recommendations for tetanus, diphtheria, pertussis (Tdap), Td boosters, hepatitis A, hepatitis B, human papilloma virus (HPV), and meningococcal vaccinations.^16,17

Live vaccines including measles mumps rubella (MMR), varicella, and zoster vaccines are in general contraindicated in immunosuppressed patients on corticosteroids, azathioprine/6-mercaptopurine, methotrexate, anti-TNF, and anti-integrin biologics. An inactive varicella-zoster vaccine will likely be available in the near future and may obviate the need for the live vaccine, which is an important development given the increased risk of zoster in patients with IBD on immunosuppression.¹⁸

Osteoporosis screening

Copyright Shawn Rocco

Both men and women with IBD have an elevated risk of osteoporosis and osteopenia as well as elevated fracture risk.¹⁹ This is related to frequent chronic corticosteroid use, chronic inflammation (high disease activity), women with low BMI, smoking, older age (women > 65, men >70), terminal ileal disease or resection in patients with CD, and proctocolectomy and ileal pouch-anal anastomosis in patients with UC. The recommendations are to obtain baseline bone density evaluation only in patients with risk factors, including young patients since osteopenia can be present at a young age. If If osteopenia is noted, then calcium (1000-1200mg daily) and vitamin D (1000-4000IU daily) supplementation can be associated with improvement in osteopenia.²⁰ If osteoporosis is noted, patients should be referred to rheumatology or endocrinology for evaluation for bisphosphonate therapy which is also associated with improved outcomes.²¹ Bone density testing should be repeated every two years in patients with osteoporosis on treatment and less frequently when there is improvement.²² Given the association of bone metabolism disorders with smoking, this is one more reason to encourage our patients to quit.

 

Skin cancer screening

Multiple studies have demonstrated that immunosuppression, especially with methotrexate and azathioprine/6-mercaptopurine (6MP) is a risk factor for the development of initial and recurrent non-melanoma skin cancer (NMSC) in IBD patients, the data for biologics are less definitive.^23-25 In addition, biologics are associated with increased risk of melanoma in IBD.²⁶ The elevated risk of skin cancer begins in the first year of treatment with thiopurines and may continue after discontinuation. On the basis of this data, screening for melanoma and NMSC is recommended in IBD patients on immunosuppression. Especially for patients on thiopurines it is reasonable for the initial dermatologist visit to occur in the first year of treatment and thereafter with at least annual visits for a full body skin examination. In addition, it is reasonable to recommend regular sunscreen use and protective clothing such as hats.

Cervical cancer screening

A recent meta-analysis shows that women with IBD on immunosuppression have an increased risk of cervical high grade dysplasia and cervical cancer.²⁷ HPV is the major risk factor for cervical cancer and is necessary for its development. The current American College of Gynecology guidelines for women on immunosuppression are to start cervical cancer screening at 21 and annual screening thereafter with Pap and HPV testing.²⁸

Smoking

Smoking has well known associations with poor outcomes in the general population such as increased risk of lung and pancreatic cancers, as well as high risk of cardiovascular disease. In addition, smoking has risks specific to IBD. In CD, smoking is associated with increased disease activity, increased risk of post-operative recurrence, and increased severity of disease.²⁹ Smoking cessation is associated with improved long-term disease outcomes and less risk.³⁰ Making it a point to regularly discuss smoking cessation and partnering with PCPs to offer evidence-based quitting aids may be one of our most significant and beneficial interventions.

Depression and anxiety

Several studies have shown high levels of depression and anxiety in IBD patients and higher levels of depression are associated with increased symptoms, clinical recurrence, poor quality of life and decreased social support.^31-33 A recent systematic review of several studies suggested that antidepressants use in IBD patients benefits their mental health and may improve their clinical course as well.³⁴ As such, screening for depression and anxiety regularly and either offering treatment or referral to psychiatrists and psychologists for further management is recommended.¹⁰

Conclusion

Patients with IBD frequently develop long-term relationships with their gastroenterologists due to their lifelong chronic disease. It is therefore incumbent on us to be attentive to issues related to IBD patients’ preventive care and collaborate with PCPs to coordinate care for our patients since many of these interventions have both short-term and long-term benefits.

Dr. Chachu is assistant professor and gastroenterologist at Duke University, Durham, N.C.

References

1. Kaplan GG, Ng SC. Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2017;152(2):313-21.e2.

2. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-17.

3. Bernstein CN, Wajda A, Svenson LW, et al. The Epidemiology of Inflammatory Bowel Disease in Canada: A Population-Based Study. The American journal of gastroenterology. 2006;101(7):1559-68.

4. Lowe AM, Roy PO, M BP, et al. Epidemiology of Crohn’s disease in Quebec, Canada. Inflammatory bowel diseases. 2009;15(3):429-35.

5. Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2007;5(12):1424-9.

6. Kappelman MD, Moore KR, Allen JK, et al. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Digestive diseases and sciences. 2013;58(2):519-25.

7. Ng SC, Kaplan G, Banerjee R, et al. 78 Incidence and Phenotype of Inflammatory Bowel Disease From 13 Countries in Asia-Pacific: Results From the Asia-Pacific Crohn’s and Colitis Epidemiologic Study 2011-2013. Gastroenterology.150(4):S21.

8. Parente JML, Coy CSR, Campelo V, et al. Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil. World Journal of Gastroenterology : WJG. 2015;21(4):1197-206.

9. Selby L, Kane S, Wilson J, et al. Receipt of preventive health services by IBD patients is significantly lower than by primary care patients. Inflammatory bowel diseases. 2008;14(2):253-8.

10. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease. The American journal of gastroenterology. 2017;112(2):241-58.

11. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. The American journal of gastroenterology. 2013;108(2):240-8.

12. Rahier JF, Papay P, Salleron J, et al. H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy. Gut. 2011;60(4):456-62.

13. deBruyn J, Fonseca K, Ghosh S, et al. Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial. Inflammatory bowel diseases. 2016;22(3):638-47.

14. Brezinschek HP, Hofstaetter T, Leeb BF, et al. Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate. Current opinion in rheumatology. 2008;20(3):295-9.

15. Kaine JL, Kivitz AJ, Birbara C, et al. Immune responses following administration of influenza and pneumococcal vaccines to patients with rheumatoid arthritis receiving adalimumab. J Rheumatol. 2007;34(2):272-9.

16. Kim DK, Riley LE, Harriman KH, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):136-8.

17. Robinson CL, Romero JR, Kempe A, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger - United States, 2017. MMWR Morbidity and mortality weekly report. 2017;66(5):134-5.

18. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflammatory bowel diseases. 2012;18(12):2392-403.

19. Card T, West J, Hubbard R, et al. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut. 2004;53(2):251-5.

20. Casals-Seoane F, Chaparro M, Mate J, et al. Clinical Course of Bone Metabolism Disorders in Patients with Inflammatory Bowel Disease: A 5-Year Prospective Study. Inflammatory bowel diseases. 2016;22(8):1929-36.

21. Melek J, Sakuraba A. Efficacy and safety of medical therapy for low bone mineral density in patients with inflammatory bowel disease: a meta-analysis and systematic review. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2014;12(1):32-44.e5.

22. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International. 2014;25(10):2359-81.

23. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141(5):1621-28.e1-5.

24. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2010;8(3):268-74.

25. Scott FI, Mamtani R, Brensinger CM, et al. Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer. JAMA dermatology. 2016;152(2):164-72.

26. Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143(2):390-9.e1.

27. Allegretti JR, Barnes EL, Cameron A. Are patients with inflammatory bowel disease on chronic immunosuppressive therapy at increased risk of cervical high-grade dysplasia/cancer? A meta-analysis. Inflammatory bowel diseases. 2015;21(5):1089-97.

28. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention. Obstetrics and gynecology. 2016;128(4):e111-30.

29. Ryan WR, Allan RN, Yamamoto T, et al. Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. American journal of surgery. 2004;187(2):219-25.

30. Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology. 2001;120(5):1093-9.

31. Fuller-Thomson E, Sulman J. Depression and inflammatory bowel disease: findings from two nationally representative Canadian surveys. Inflammatory bowel diseases. 2006;12(8):697-707.

32. Walker EA, Gelfand MD, Gelfand AN, et al. The relationship of current psychiatric disorder to functional disability and distress in patients with inflammatory bowel disease. General hospital psychiatry. 1996;18(4):220-9.

33. Mikocka-Walus A, Pittet V, Rossel J-B, et al. Symptoms of Depression and Anxiety Are Independently Associated With Clinical Recurrence of Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology.14(6):829-35.e1.

34. Macer BJD, Prady SL, Mikocka-Walus A. Antidepressants in Inflammatory Bowel Disease: A Systematic Review. Inflammatory bowel diseases. 2017;23(4):534-50.

 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

AP is the one of the most common gastrointestinal disorders requiring hospitalization, accounting for roughly 270,000 admissions annually in the U.S., which translates into a $2.6 billion annual health care expenditure.
 

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

As with any disorder, management starts with prevention. Primary prevention of AP has only been well studied in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis (PEP) is the most common and arguably the most dreaded complication of ERCP with reported incidence of approximately 10%⁷. Several medications and endoscopic interventions have been assessed for the prevention of PEP. Of these, placement of prophylactic pancreatic duct stents^8,9 and administration of rectal nonsteroidal anti-inflammatory drugs, especially indomethacin, have shown significant benefit in reducing risk for PEP^10,11. It is unclear at this point whether rectal indomethacin alone (without pancreatic duct stenting) is sufficient in patients at high risk for PEP. The SVI (Stent Vs. Indomethacin) trial¹², an ongoing multicenter randomized controlled trial, aims to answer this specific question.

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

There is a plethora of scoring systems developed to predict AP severity and outcomes at presentation and/or within the first 24 hours. These include the Ranson’s criteria described in 1974, the APACHE-II (Acute Physiology and Chronic Health Evaluation II), BISAP (Bedside Index of Severity in Acute Pancreatitis) scores, and others. They all have similar, but only modest, accuracy^16,17. Experts recommend¹⁸ that the Systemic Inflammatory Response Syndrome (SIRS) may be the most useful score in daily clinical practice, given that all of its four parameters are readily available (temperature, heart rate, respiratory rate, and white blood cell count) and the score is easy to calculate. Recent studies suggest that admission hematocrit and rise in blood urea nitrogen (BUN) at 24 hours are as accurate as more complex scoring systems in predicting severe disease¹⁹.

 

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

What remains debatable is the amount and type of fluid administered. Lactated Ringers (LR) is likely the optimal solution, based on a small prospective randomized-controlled study showing that administration of LR reduced SIRS compared with saline²⁴. Endpoints to guide adequacy of fluid resuscitation in the first 24-48 hours include measurement of urine output (at least 0.5 mL/kg per hour)²⁵, decrease in hematocrit²⁶ and BUN levels²⁷.

 

 

Selecting level of care and ICU management

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Urgent ERCP (within 24-48 hours of admission) in patients with biliary AP is indicated³¹ when there is strong clinical suspicion for concomitant cholangitis and/or evidence of ongoing biliary obstruction (secondary to choledocholithiasis) on imaging. Currently, predicted severe AP of biliary etiology does not constitute an indication of urgent ERCP in the absence of the above parameters³².

 

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

The etiology of AP can be determined in the majority of patients. In many instances, recurrence can be prevented, i.e., in biliary or alcoholic etiologies. In patients with mild biliary AP, evidence supports³⁷ the performance of cholecystectomy during the index admission. In cases of severe biliary AP complicated by pancreatic necrosis and/or peripancreatic fluid collections, cholecystectomy should be delayed for a few weeks until the collections regress or mature³⁸. In poor surgical candidates, ERCP with biliary sphincterotomy offers an alternative, but less effective, means of reducing the risk of recurrent attacks in patients with biliary AP³⁹. In subjects with first AP attack of alcoholic etiology, counseling focusing on alcohol cessation has shown to reduce risk of recurrences⁴⁰. Similarly, appropriate plans to treat and follow-up underlying metabolic etiologies (hypercalcemia and HTG) should be preferably instituted prior to the patients’ discharge.

 

 

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

It is only the mature PFCs, which are symptomatic resulting in abdominal pain, nausea, early satiety, gastric outlet obstruction, failure to thrive, and/or biliary obstruction, that need to be drained/debrided⁴². Minimally invasive approaches have shown to result in better outcomes when compared to open laparotomy. Minimally invasive approaches include placement of percutaneous drainage catheters by interventional radiology (retroperitoneal approach preferred when feasible), endoscopic drainage/debridement, laparoscopy, and retroperitoneal necrosectomy following a step-up approach⁴³.

 

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

 

Management of pancreatic necrosis

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Infectious complications are the major cause of late mortality in AP. The predominant source is bacterial translocation from the GI tract^47,48. Infected pancreatic necrosis should be suspected in patients with imaging evidence of pancreatic or extrapancreatic necrosis, who have a sudden deterioration in clinical status, typically 2-3 weeks after onset of symptoms or if gas bubbles are seen within a necrotic collection (Figure 2). When infected pancreatic necrosis is suspected or established, antibiotics such as carbapenems, fluoroquinolones, metronidazole, and cephalosporin should be started, which have better penetrance into ischemic pancreatic tissue. CT guided aspiration has lost much of its utility, since there has been a paradigm shift to delaying drainage of infected (suspected or established) pancreatic necrosis. A negative or positive CT aspirate does not dictate timing of intervention and is only recommended if a fungal or drug resistant infection is suspected¹⁵. As mentioned above, when debridement of an infected necroma is contemplated, the two guiding principles are to delay drainage and use minimally invasive approaches.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

 

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.
 

 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

AP is the one of the most common gastrointestinal disorders requiring hospitalization, accounting for roughly 270,000 admissions annually in the U.S., which translates into a $2.6 billion annual health care expenditure.
 

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

As with any disorder, management starts with prevention. Primary prevention of AP has only been well studied in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis (PEP) is the most common and arguably the most dreaded complication of ERCP with reported incidence of approximately 10%⁷. Several medications and endoscopic interventions have been assessed for the prevention of PEP. Of these, placement of prophylactic pancreatic duct stents^8,9 and administration of rectal nonsteroidal anti-inflammatory drugs, especially indomethacin, have shown significant benefit in reducing risk for PEP^10,11. It is unclear at this point whether rectal indomethacin alone (without pancreatic duct stenting) is sufficient in patients at high risk for PEP. The SVI (Stent Vs. Indomethacin) trial¹², an ongoing multicenter randomized controlled trial, aims to answer this specific question.

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

There is a plethora of scoring systems developed to predict AP severity and outcomes at presentation and/or within the first 24 hours. These include the Ranson’s criteria described in 1974, the APACHE-II (Acute Physiology and Chronic Health Evaluation II), BISAP (Bedside Index of Severity in Acute Pancreatitis) scores, and others. They all have similar, but only modest, accuracy^16,17. Experts recommend¹⁸ that the Systemic Inflammatory Response Syndrome (SIRS) may be the most useful score in daily clinical practice, given that all of its four parameters are readily available (temperature, heart rate, respiratory rate, and white blood cell count) and the score is easy to calculate. Recent studies suggest that admission hematocrit and rise in blood urea nitrogen (BUN) at 24 hours are as accurate as more complex scoring systems in predicting severe disease¹⁹.

 

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

What remains debatable is the amount and type of fluid administered. Lactated Ringers (LR) is likely the optimal solution, based on a small prospective randomized-controlled study showing that administration of LR reduced SIRS compared with saline²⁴. Endpoints to guide adequacy of fluid resuscitation in the first 24-48 hours include measurement of urine output (at least 0.5 mL/kg per hour)²⁵, decrease in hematocrit²⁶ and BUN levels²⁷.

 

 

Selecting level of care and ICU management

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Urgent ERCP (within 24-48 hours of admission) in patients with biliary AP is indicated³¹ when there is strong clinical suspicion for concomitant cholangitis and/or evidence of ongoing biliary obstruction (secondary to choledocholithiasis) on imaging. Currently, predicted severe AP of biliary etiology does not constitute an indication of urgent ERCP in the absence of the above parameters³².

 

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

The etiology of AP can be determined in the majority of patients. In many instances, recurrence can be prevented, i.e., in biliary or alcoholic etiologies. In patients with mild biliary AP, evidence supports³⁷ the performance of cholecystectomy during the index admission. In cases of severe biliary AP complicated by pancreatic necrosis and/or peripancreatic fluid collections, cholecystectomy should be delayed for a few weeks until the collections regress or mature³⁸. In poor surgical candidates, ERCP with biliary sphincterotomy offers an alternative, but less effective, means of reducing the risk of recurrent attacks in patients with biliary AP³⁹. In subjects with first AP attack of alcoholic etiology, counseling focusing on alcohol cessation has shown to reduce risk of recurrences⁴⁰. Similarly, appropriate plans to treat and follow-up underlying metabolic etiologies (hypercalcemia and HTG) should be preferably instituted prior to the patients’ discharge.

 

 

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

It is only the mature PFCs, which are symptomatic resulting in abdominal pain, nausea, early satiety, gastric outlet obstruction, failure to thrive, and/or biliary obstruction, that need to be drained/debrided⁴². Minimally invasive approaches have shown to result in better outcomes when compared to open laparotomy. Minimally invasive approaches include placement of percutaneous drainage catheters by interventional radiology (retroperitoneal approach preferred when feasible), endoscopic drainage/debridement, laparoscopy, and retroperitoneal necrosectomy following a step-up approach⁴³.

 

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

 

Management of pancreatic necrosis

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Infectious complications are the major cause of late mortality in AP. The predominant source is bacterial translocation from the GI tract^47,48. Infected pancreatic necrosis should be suspected in patients with imaging evidence of pancreatic or extrapancreatic necrosis, who have a sudden deterioration in clinical status, typically 2-3 weeks after onset of symptoms or if gas bubbles are seen within a necrotic collection (Figure 2). When infected pancreatic necrosis is suspected or established, antibiotics such as carbapenems, fluoroquinolones, metronidazole, and cephalosporin should be started, which have better penetrance into ischemic pancreatic tissue. CT guided aspiration has lost much of its utility, since there has been a paradigm shift to delaying drainage of infected (suspected or established) pancreatic necrosis. A negative or positive CT aspirate does not dictate timing of intervention and is only recommended if a fungal or drug resistant infection is suspected¹⁵. As mentioned above, when debridement of an infected necroma is contemplated, the two guiding principles are to delay drainage and use minimally invasive approaches.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

 

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.
 

 

Historical perspective

The term “pancreas” derives its name from the Greek words pan (all) and kreas (flesh). Understanding pancreas physiology was first attempted in the 17th century by Regnier de Graaf^1. Giovanni Morgagni is credited with the first description of the syndrome of acute pancreatitis (AP) in 1761². Reginald Huber Fitz proposed the first classification of AP into hemorrhagic, gangrenous, and suppurative types in 1889³. The distinction of acute from chronic pancreatitis was not well described until the middle of the 20th century when Mandred W. Comfort gave a detailed account of chronic relapsing pancreatitis in 1946⁴.

AP is the one of the most common gastrointestinal disorders requiring hospitalization, accounting for roughly 270,000 admissions annually in the U.S., which translates into a $2.6 billion annual health care expenditure.
 

Diagnosis and classification of severity

The diagnosis of AP is based on the presence of two of the three following criteria: typical abdominal pain (severe, upper abdominal pain frequently radiating to the back), serum amylase and/or lipase levels greater than 3 times the upper limit of normal, and/or characteristic imaging findings.

The original 1992 Atlanta classification provided the first blueprint to standardize how severity of AP was defined⁵. Over the years, better understanding of AP pathophysiology and its complications led to a greater focus on local and systemic determinants of severity⁶ and eventually the Revised Atlanta Classification (RAC) in 2013 (Table 1).
 

Management of acute pancreatitis

Prevention

As with any disorder, management starts with prevention. Primary prevention of AP has only been well studied in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis (PEP) is the most common and arguably the most dreaded complication of ERCP with reported incidence of approximately 10%⁷. Several medications and endoscopic interventions have been assessed for the prevention of PEP. Of these, placement of prophylactic pancreatic duct stents^8,9 and administration of rectal nonsteroidal anti-inflammatory drugs, especially indomethacin, have shown significant benefit in reducing risk for PEP^10,11. It is unclear at this point whether rectal indomethacin alone (without pancreatic duct stenting) is sufficient in patients at high risk for PEP. The SVI (Stent Vs. Indomethacin) trial¹², an ongoing multicenter randomized controlled trial, aims to answer this specific question.

Determination of etiology

The most common causes of AP are gallstones and alcohol, accounting for more than two-thirds of all cases¹³. Other etiologies include hypertriglyceridemia, ERCP, drugs induced, familial/hereditary, and post-traumatic. Initial work up includes a thorough history to quantify alcohol consumption and assess for recently started medications, measurement of liver injury tests¹⁴ and triglyceride levels, and performance of a transabdominal ultrasound to evaluate for biliary dilation, chole- and choledocholithiasis¹⁵.

Assessment of disease severity

There is a plethora of scoring systems developed to predict AP severity and outcomes at presentation and/or within the first 24 hours. These include the Ranson’s criteria described in 1974, the APACHE-II (Acute Physiology and Chronic Health Evaluation II), BISAP (Bedside Index of Severity in Acute Pancreatitis) scores, and others. They all have similar, but only modest, accuracy^16,17. Experts recommend¹⁸ that the Systemic Inflammatory Response Syndrome (SIRS) may be the most useful score in daily clinical practice, given that all of its four parameters are readily available (temperature, heart rate, respiratory rate, and white blood cell count) and the score is easy to calculate. Recent studies suggest that admission hematocrit and rise in blood urea nitrogen (BUN) at 24 hours are as accurate as more complex scoring systems in predicting severe disease¹⁹.

 

Fluid resuscitation

Despite extensive research and trials using medications such as ulinastatin, octreotide, pentoxifylline, gabexate, N-acetyl cysteine, steroids, IL-10, and antibiotics²⁰, no pharmacologic agent has been shown to significantly alter the clinical course/outcomes of AP.

Adequate intravenous hydration remains the cornerstone of early management in AP²¹. Studies have demonstrated that increased intestinal permeability, secondary to reduced intestinal capillary microcirculation, leads to bacterial translocation and development of SIRS²². Intestinal microcirculation does not become as readily impaired, and there is a certain “latency” to its onset, from the insult that triggers pancreatitis. This gives rise to the concept of a “golden window” of 12-24 hours from the insult to potentially reverse such changes and prevent organ dysfunction. It has been shown that patients who are adequately resuscitated with intravenous fluids have lower risk for local and systemic complications²³.

What remains debatable is the amount and type of fluid administered. Lactated Ringers (LR) is likely the optimal solution, based on a small prospective randomized-controlled study showing that administration of LR reduced SIRS compared with saline²⁴. Endpoints to guide adequacy of fluid resuscitation in the first 24-48 hours include measurement of urine output (at least 0.5 mL/kg per hour)²⁵, decrease in hematocrit²⁶ and BUN levels²⁷.

 

 

Selecting level of care and ICU management

Patients with predicted severe AP or those with persistent SIRS despite initial fluid resuscitation should be managed in a closely monitored unit, ideally an ICU. Patients with impending respiratory failure require mechanical ventilation, renal failure complicated by metabolic acidosis and/or hyperkalemia requires hemodialysis, and cardiovascular shock requires the initiation of vasopressors and continuous monitoring of blood pressure via an arterial line. A special entity that requires ICU level care is hypertriglyceridemia (HTG)-induced severe AP. HTG should be considered as the etiology of AP in certain clinical scenarios²⁸: previous history of HTG, poorly controlled diabetes mellitus, history of significant alcohol use, third trimester of pregnancy, and use of certain medications associated with HTG such as oral estrogens, tamoxifen, and propofol. Levels of triglyceride greater than 1000 mg/dL strongly point toward HTG being the etiology.

Plasmapheresis, which filters and removes triglycerides from plasma, has been reported as an efficient treatment in such patients based on case series^29,30. At this time its use may only be justified in patients with predicted severe AP from HTG, preferably within the first 24 hours of presentation.


Urgent ERCP

Urgent ERCP (within 24-48 hours of admission) in patients with biliary AP is indicated³¹ when there is strong clinical suspicion for concomitant cholangitis and/or evidence of ongoing biliary obstruction (secondary to choledocholithiasis) on imaging. Currently, predicted severe AP of biliary etiology does not constitute an indication of urgent ERCP in the absence of the above parameters³².

 

Nutrition

Recovery of the gut function is often delayed for several days or weeks in patients with severe AP. Studies have shown that prolonged fasting in such circumstances leads to malnutrition and worse prognosis^33,34. Enteral nutrition via a nasogastric (NG) or nasojejunal (NJ) tube is the preferred route of nutritional support, as it is associated with lower risk of infection, multi-organ failure, and mortality when compared to total parenteral nutrition³³.

The question of whether NJ feeding offers any additional advantages over NG feeding has not been clearly answered with a recent randomized trial showing NG feeds not to be inferior to NJ feeds³⁵. In regards to the timing of initiation of enteral nutrition, early nasoenteric feeding within 24 hours from presentation was found not to be superior compared to on-demand feeding in patients with predicted severe AP³⁶.


Strategies to decrease risk of recurrent attacks

The etiology of AP can be determined in the majority of patients. In many instances, recurrence can be prevented, i.e., in biliary or alcoholic etiologies. In patients with mild biliary AP, evidence supports³⁷ the performance of cholecystectomy during the index admission. In cases of severe biliary AP complicated by pancreatic necrosis and/or peripancreatic fluid collections, cholecystectomy should be delayed for a few weeks until the collections regress or mature³⁸. In poor surgical candidates, ERCP with biliary sphincterotomy offers an alternative, but less effective, means of reducing the risk of recurrent attacks in patients with biliary AP³⁹. In subjects with first AP attack of alcoholic etiology, counseling focusing on alcohol cessation has shown to reduce risk of recurrences⁴⁰. Similarly, appropriate plans to treat and follow-up underlying metabolic etiologies (hypercalcemia and HTG) should be preferably instituted prior to the patients’ discharge.

 

 

Management of peripancreatic fluid collections

Patients with AP frequently develop peripancreatic fluid collections (PFCs). Based on the revised Atlanta classification, those are categorized into four types (Table 2, Figures 1-4).

The majority of acute PFCs in patients without evidence of pancreatic necrosis regress within a few weeks and thus intervention is not indicated early in the disease course. Current literature supports delaying the drainage/debridement of such collections for several weeks. The mortality from interventions decreases as the time to intervention from onset of symptoms increases⁴¹. Delaying intervention gives more time for recovery from systemic complications and allows the encapsulating wall and contents to organize further.

It is only the mature PFCs, which are symptomatic resulting in abdominal pain, nausea, early satiety, gastric outlet obstruction, failure to thrive, and/or biliary obstruction, that need to be drained/debrided⁴². Minimally invasive approaches have shown to result in better outcomes when compared to open laparotomy. Minimally invasive approaches include placement of percutaneous drainage catheters by interventional radiology (retroperitoneal approach preferred when feasible), endoscopic drainage/debridement, laparoscopy, and retroperitoneal necrosectomy following a step-up approach⁴³.

 

While surgery is still an option for patients with symptomatic mature PFCs, endoscopic ultrasound-guided drainage in expert hands has been shown to be cost effective, with shorter hospital stay and even decreased risk of cyst recurrence compared with surgical cyst-gastrostomy creation⁴⁴. Ultrasound or computed tomography-guided drainage of such collections with a percutaneous catheter is an equally efficacious option when compared to the endoscopic approach. However, patients undergoing endotherapy require fewer procedures and imaging studies and shorter length of stay⁴⁵ when compared with radiological interventions.

 

Management of pancreatic necrosis

Although this topic has generated much debate, the majority of available evidence shows no clinical benefit from using prophylactic antibiotics to prevent infection in pancreatic necrosis⁴⁶.

Infectious complications are the major cause of late mortality in AP. The predominant source is bacterial translocation from the GI tract^47,48. Infected pancreatic necrosis should be suspected in patients with imaging evidence of pancreatic or extrapancreatic necrosis, who have a sudden deterioration in clinical status, typically 2-3 weeks after onset of symptoms or if gas bubbles are seen within a necrotic collection (Figure 2). When infected pancreatic necrosis is suspected or established, antibiotics such as carbapenems, fluoroquinolones, metronidazole, and cephalosporin should be started, which have better penetrance into ischemic pancreatic tissue. CT guided aspiration has lost much of its utility, since there has been a paradigm shift to delaying drainage of infected (suspected or established) pancreatic necrosis. A negative or positive CT aspirate does not dictate timing of intervention and is only recommended if a fungal or drug resistant infection is suspected¹⁵. As mentioned above, when debridement of an infected necroma is contemplated, the two guiding principles are to delay drainage and use minimally invasive approaches.

Vascular complications

Vascular complications such as splanchnic vein thrombosis can occur in up to a quarter of AP patients⁴⁹. Anticoagulation is not usually indicated unless thrombosis is extensive and causes bowel ischemia. Arterial pseudoaneurysms are rare but life threatening complications of AP. They typically require interventional radiology guided coil embolization to prevent massive bleeding⁵⁰.

Abdominal compartment syndrome

Abdominal compartment syndrome is an end result of third spacing of fluid into the abdominal cavity secondary to inflammation and fluid resuscitation in severe pancreatitis. Abdominal pressure in patients can be monitored by measuring bladder pressures. Intra-abdominal hypertension is defined as a sustained pressure greater than 12 mm Hg, while abdominal compartment syndrome is defined as sustained intra-abdominal pressure greater than 20 mm Hg with new organ failure⁵¹. Intra-abdominal hypertension (IAH) is present in up to 75% of patients with severe AP. While all conservative measures to prevent development or worsening of IAH should be implemented (adequate sedation, decompression of bowel in patients with ileus, etc.), current guidelines do not recommend aggressive interventions to treat it. On the other hand, abdominal compartment syndrome is a life-threatening complication that requires urgent intervention to decrease intra-abdominal pressure, such as percutaneous drain placement or surgical fasciotomy^52,53.

Conclusion

The key principles in the management of acute pancreatitis are aggressive hydration and preventing development of end organ failure. In the last two decades there has been a paradigm shift in the guidelines for management of peripancreatic fluid collections and pancreatic necrosis. When feasible, drainage of these collections should be delayed and be performed using minimally invasive interventions. There is still an urgent need for developing and testing disease-specific treatments targeting control of the inflammatory response in the early phase of acute pancreatitis and prevention of development of severe disease with end-organ dysfunction.

Dr. Gulati is a gastroenterology and hepatology fellow at Allegheny Health Network, Pittsburgh, and Dr. Papachristou is professor of medicine, University of Pittsburgh School of Medicine, Pittsburgh.

References

1. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Chapter 55, 923-33.

2. Morgagni G.B. [Fie Books on the Seats and Causes of Diseases as Discovered by the Anatomist]. Venice, Italy: Typographia Remondiniana;1761.

3. Fitz R.H. Boston Med Surg J. 1889;120:181-8.

4. Comfort M., Gambill E., Baggesnstoss A. Gastroenterology. 1946;6:238-76.

5. Bollen T.L., van Santvoort H.C., Besselink M.G., et al. Br J Surg. 2008;95:6–21.

6. Dellinger E.P., Forsmark C.E., Layer P., et al. Ann Surg. 2012 Dec;256[6]:875-80.

7. Kochar B., Akshintala V.S., Afghani E., et al. Gastrointest Endosc. 2015 Jan;81[1]:143-9.

8. Choudhary A., Bechtold M.L., Arif M., et al. Gastrointest Endosc. 2011 Feb;73[2]:275-82.

9. Shi Q.Q., Ning X.Y., Zhan L.L., Tang G.D., Lv X.P. World J Gastroenterol. 2014 Jun 14;20[22]:7040-8.

10. Elmunzer B.J., Waljee A.K., Elta G.H., Taylor J.R., Fehmi S.M., Higgins P.D. Gut. 2008 Sep;57[9]:1262-7.

11. Sethi S., Sethi N., Wadhwa V., Garud S., Brown A. Pancreas. 2014 Mar;43[2]:190-7. 
12. Elmunzer B.J., Serrano J., Chak A., et al. Trials. 2016 Mar 3;17[1]:120.

13. Lowenfels A.B., Maisonneuve P., Sullivan T. Curr Gastroenterol Rep. 2009;11:97-103.

14. Agarwal N., Pitchumoni C.S., Sivaprasad A.V. Am J Gastroenterol. 1990;85:356-66.

15. Tenner S., Baillie J., DeWitt J. Vege S.S. Am J Gastroenterol. 2013;108:1400-15.

16. Papachristou G.I., Muddana V., Yadav D., et al. Am J Gastroenterol. 2010;105:435-41.

17. Mounzer R., et al. Gastroenterology 2012;142:1476-82.

18. Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

19. Koutroumpakis E., Wu B.U., Bakker O.J., et al. Am J Gastroenterol. 2015 Dec;110[12]:1707-16.

20. Bang U.C., Semb S., Nojgaard C., Bendtsen F. World J Gastroenterol. 2008 May 21;14[19]:2968-76.

21. Warndorf M.G., Kurtzman J.T., Bartel M.J., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:705-9.

22. Hotz H.G., Foitzik T., Rohweder J., et al. J Gastrointest Surg. 1998 Nov-Dec;2[6]:518-25.

23. Brown A., Baillargeon J.D., Hughes M.D., et al. Pancreatology 2002;2:104-7.

24. Wu B.U., Hwang J.Q., Gardner T.H., et al. Clin Gastroenterol Hepatol. 2011 Aug;9[8]:710-7.

25. Forsmark C.E., Baillie J., AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. Gastroenterology. 2007 May;132[5]:2022-44.

26. Lankisch P.G., Mahlke R., Blum T., et al. Am J Gastroenterol. 2001;96:2081-5.

27. Wu B.U., Johannes R.S., Sun X., et al. Gastroenterology 2009;137:129-35.

28. Scherer J., Singh V.P., Pitchumoni C.S., Yadav D. J Clin Gastroenterol. 2014 Mar;48[3]:195-203.

29. Gubensek J., Buturovic-Ponikvar J., Romozi K., Ponikvar R. PLoS One. 2014 Jul 21;9[7]:e102748.

30. Chen J.H., Yeh J.H., Lai H.W., Liao C.S. World J Gastroenterol. 2004 Aug 1;10[15]:2272-4.

31. Tse F., Yuan Y. Cochrane Database Syst Rev. 2012 May 16;[5]:CD009779.

32. Folsch U.R., Nitsche R., Ludtke R., et al. N Engl J Med. 1997;336:237-42.

33. Al-Omran M., Albalawi Z.H., Tashkandi M.F., Al-Ansary L.A. Cochrane Database Syst Rev. 2010 Jan 20;[1]:CD002837.

 

34. Li J.Y., Yu T., Chen G.C., et al. PLoS One. 2013;8[6]:e64926.

35. Singh N., Sharma B., Sharma M., et al. Pancreas. 2012 Jan;41[1]:153-9.

36. Bakker O.J., van Brunschot S., van Santvoort H.C., et al. N Engl J Med. 2014 Nov 20;371[21]:1983-93.

37. Van Baal M.C., Besselink M.G., Bakker O.J., et al. Ann Surg. 2012;255:860–6.

38. Nealon W.H., Bawduniak J., Walser E.M. Ann Surg. 2004 Jun;239[6]:741-9.

39. Sanjay P., Yeeting S., Whigham C., Judson H., Polignano F.M., Tait I.S. Surg Endosc. 2008 Aug;22[8]:1832-7.

40. Nordback I., Pelli H., Lappalainen-Lehto R., Järvinen S., Räty S., Sand J. Gastroenterology. 2009 Mar;136[3]:848-55.

41. Besselink M.G., Verwer T.J., Schoenmaeckers E.J., et al. Arch Surg. 2007;142:1194-201.

42. Besselink M., van Santvoort H., Freeman M. et al. Pancreatology. 2013 Jul-Aug;13(4 Suppl 2):e1-15.

43. Hjalmar C., van Santvoort, H., Besselink M.G., et al. N Engl J Med. 2010;362:1491-502.

44. Varadarajulu S., Bang J.Y., Sutton B.S., et al. Gastroenterology. 2013;145:583-90.e1.

45. Akshintala V.S., Saxena P., Zaheer A., et al. Gastrointest Endosc. 2014 Jun;79[6]:921-8.

46. Jiang K, Huang W, Yang XN., et al. World J Gastroenterol. 2012;18:279–84.

47. Dervenis C., Smailis D., Hatzitheoklitos E. J Hepatobiliary Pancreat Surg. 2003;10[6]:415Y418.

48. Gloor B., Muller C.A., Worni M., et al. Arch Surg. 2001;136[5]:592Y596.

49. Nadkarni N.A., Khanna S., Vege S.S. Pancreas. 2013 Aug;42[6]:924-31.

50. Marshall G.T., Howell D.A., Hansen B.L., Amberson S.M., Abourjaily G.S., Bredenberg C.E. Arch Surg. 1996 Mar;131[3]:278-83.

51. Malbrain M.L., Cheatham M.L., Kirkpatrick A., et al. Intensive Care Med. 2006 Nov;32[11]:1722-32.

52. De Waele J.J. Leppaniemi A.K. World J Surg. 2009;33:1128-33.

53. Kirkpatrick A.W., Roberts D.J., De W.J., et al. Intensive Care Med. 2013 Jul;39[7]1190-206.